Novel anticonvulsant derivative salts

ABSTRACT

The invention relates to novel pharmaceutically acceptable salts of anticonvulsant derivatives, processes for preparation of and pharmaceutical compositions containing said salts, useful in the treatment of epilepsy.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional application Ser.No. 60/303,962 filed Jul., 09, 2001, the contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutically acceptable saltsof anticonvulsant derivatives, processes for preparation of andpharmaceutical compositions containing said salts.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,513,006, which is hereby incorporated by reference,discloses a class of novel anti-epileptic compounds. One of thesecompounds, 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosesulfamate, known as topiramate, has been demonstrated in clinical trialsof human epilepsy to be effective as adjunctive therapy or asmonotherapy in treating simple and complex partial seizure andsecondarily generalized seizures (E. Faught, B. J. Wilder, R. E. Ramsey,R. A. Reife, L. D. Kramer, G. Pledger, R. M. Karim, et al., Epilepsia,36 (S4) 33, (1995); S. K. Sachdeo, R. C. Sachdeo, R. A. Reife, P. Limand G. Pledger, Epilepsia, 36 (S4) 33, (1995)). U.S. Pat. No. 4,513,006,U.S. Pat. No. 5,242,942, and U.S. Pat. No. 5,384,327, which are herebyincorporated by reference, disclose processes for the preparation ofthese novel anti-epileptic compounds.

Topiramate is currently marketed for the treatment of simple and complexpartial seizure epilepsy with or without secondary generalized seizuresin Great Britain, Finland, the United States and Sweden and applicationsfor regulatory approval are presently pending in numerous countriesthroughout the world.

Ehrenberg et al in U.S. Pat. No. 5,998,380 disclose pharmaceuticallyacceptable derivatives of the following formula (A)

wherein the substituents are a described in U.S. Pat. No. 5,998,380. Bypharmaceutically acceptable derivative is meant any pharmaceuticallyacceptable ester or salt of such ester of the compounds of the formula(A) or any other compounds which upon administration to the recipient iscapable of providing (directly or indirectly) a compound of the formula(A) or an anti-migraine active metabolite or residue thereof.

Pharmaceutically acceptable salts of the compounds of the formula (A)include those derived from pharmaceutically acceptable, inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, formic, benzoic, malonic,naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such asoxalic acid, while not in themselves pharmaceutically acceptable, may beuseful in the preparation of salts useful as intermediates in obtainingcompounds useful in the method of the patent and their pharmaceuticallyacceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g. sodium),alkaline earth metal (e.g. magnesium) ammonium and NR₄ (where R isC₁₋₄alkyl) salts.

McElroy, S. L. in PCT application WO 00/50020 disclose pharmaceuticallyacceptable salts of compounds of the following formula (B)

wherein the substituents are as described in PCT application WO00/50020. Pharmaceutically acceptable salts of the compounds of theformula (B) include, for example, alkali metal salts, such as sodium andpotassium; ammonium salts, monoalkylammmonium salts; dialkylammoniumsalts; trialkylammonium salts; tetraalkylammonium salts; andtromethamine salts. Hydrates and other solvates of the compound of theformula (B) are also included within the scope of compounds.

Pharmaceutically acceptable salts of the compounds of formula (B) can beprepared by reacting the compound of the formula (B) with an appropriatebase and recovering the salt.

Dewey et al, in PCT application WO 00/07583 disclose pharmaceuticallyacceptable salts of topiramate. As defined in the specification,pharmaceutically acceptable salts include those salt-forming acids andbases which do not substantially increase the toxicity of the compound.Some examples of suitable salts include salts of mineral acids such ashydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric,nitric and sulfuric acids, as well as salts of organic acids such astartaric, acetic, citric, malic, benzoic, glycollic, gluconic, gulonic,succinic, arylsulfonic, eg. p-toluenesulfonic acids, and the like.

We now describe novel salt forms of anticonvulsant derivatives,including novel salt forms of topiramate, which forms are suitable foruse in the preparation of pharmaceutical formulations.

SUMMARY OF THE INVENTION

The present invention relates to novel salt forms of a compound offormula (I)

wherein the salts are formed at the sulfamate group of the compound offormula (I). Preferably the salts are formed by displacing at least onehydrogen on the sulfamate group of the compound of formula (I). Morepreferably, the salts are formed by displacing one hydrogen on thesulfamate group of the compound of formula (I).

In an embodiment, the present invention is directed to novel salt formsof topiramate, a compound of formula (Ia)

wherein the salts are formed at the sulfamate group of the compound offormula (Ia).

In an embodiment of the invention are alkali metal and magnesium saltsof the compound of formula (I), formed at the sulfamate group of thecompound of formula (I). Preferably, the compound of formula (I) is thecompound of formula (Ia).

In an embodiment of the invention is a sodium salt of the compound offormula (I). In another embodiment of the invention is a potassium saltof the compound of formula (I). In still another embodiment of theinvention is a lithium salt of the compound of formula (I). In stillanother embodiment of the invention is a magnesium salt of the compoundof formula (I).

In an embodiment of the invention is a sodium salt of topiramate (thecompound of formula (Ia)). In another embodiment of the invention is apotassium salt of topiramate (the compound of formula (Ia)). In stillanother embodiment of the invention is a lithium salt of topiramate (thecompound of formula (Ia)). In still another embodiment of the inventionis a magnesium salt of topiramate (the compound of formula (Ia)).

In an aspect, the present invention relates to a process for preparingsaid salts of the compound of formula (I). In another aspect, thepresent invention relates to a process for preparing said salts oftopiramate (the compound of formula (Ia)).

In a further aspect of the present invention are novel crystalline formsof the sodium and potassium salts of topiramate, the compound of formula(Ia).

Illustrative of the invention is a pharmaceutical composition comprisingany of the salts described above and a pharmaceutically acceptablecarrier.

Exemplifying the invention is a pharmaceutical composition made bycombining any of the salts described above and a pharmaceuticallyacceptable carrier.

An example of the invention is a process for making a pharmaceuticalcomposition comprising combining any of the salts described above and apharmaceutically acceptable carrier.

Another example of the invention is the use of any of the saltsdescribed herein in the preparation of a medicament for treatingepilepsy, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, unless otherwise noted, the term “anti-solvent” shallrefer to a solvent which does not dissolve a specific substance and isadded to a solution of said substance to cause precipitation of saidsubstance.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, includes straight and branched carbon chains. Forexample, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwisenoted, “lower” when used with alkyl means a carbon chain composition of1-4 carbon atoms.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like. Unless otherwise noted, “lower” when used withalkoxy means an oxygen ether radical of a carbon chain composition of1-4 carbon atoms.

The novel crystalline salts forms of the compound of formula (Ia) of thepresent invention were characterized by their respective X-ray powderdiffraction (XRD) patterns utilizing a Phillips PW3710 based X-raypowder diffractometer, using a long fine-focus Cu K_(α) radiation sourceand the following system conditions:

-   -   a) CuKα radiation, 1.5406 Å, 40 KV, 30 mA    -   b) Optics: 1/12° divergence slit 0.2 mm receiving slit    -   c) Xenon gas-filled proportional detector    -   d) Scan 2 to 35°02θ at a scan speed of 0.0163°2θ/sec (step side        0.020°2θ)    -   e) Conventional Philips sample holder

The present invention is directed to novel salts of a compound offormula (I), preferably, novel salt forms of a compound of formula (Ia);novel crystalline forms of the sodium and potassium salts of thecompound of formula (Ia); and processes for the preparation of salts ofa compound of formula (I). Particularly, the novel salts of a compoundof formula (I) are alkali metals or magnesium salts, wherein an alkalimetal or magnesium cation displaces at least one hydrogen atom,preferably one hydrogen atom, on the sulfamate portion of the compoundof formula (I). More particularly, the salts are sodium, potassium,lithium and magnesium salts of a compound of formula (I), wherein asodium, potassium, lithium or magnesium cation displaces at least onehydrogen atom, preferably one hydrogen atom, on the sulfamate portion ofthe compound of formula (I).

In a preferred embodiment of the present invention, the compound offormula (I) is the compound of formula (Ia).

In an embodiment of the present invention, is a process for preparingthe alkali metal salts of a compound of formula (I), comprising

a.) reacting the compound of formula (I) with an alkali metal hydride,an alkali metal hydroxide, an alkali metal lower alkoxide, an alkalimetal amide, or if the alkali metal is lithium alternatively with analkyl lithium; and

b.) precipitating the product.

More particularly, the compound of formula (I) is reacted with an alkalimetal hydride, under anhydrous conditions; or with an alkali metalhydroxide; or with an alkali metal lower alkoxide, preferably underanhydrous conditions; or with an alkali metal amide, under anhydrousconditions; in an organic solvent; or when the alkali metal is lithiumalternatively with an alkyl lithium, under anhydrous conditions; and theproduct is precipitated to yield the corresponding alkali metal salt.

In an embodiment of the present invention, is a process for preparingthe magnesium salts of a compound of formula (I), comprising

a.) reacting the compound of formula (I) with a magnesium loweralkoxide; under anhydrous conditions; and

b.) precipitating the product.

More particularly, the compound of formula (I) is reacted with amagnesium lower alkoxide, under anhydrous conditions; in an organicsolvent; and the product is precipitated to yield the correspondingmagnesium salt.

In one embodiment of the invention is a sodium salt of a compound offormula (I). Preferably, the sodium salt of the compound of formula (I)is a salt wherein a sodium cation displaces one of the hydrogen atoms ofthe sulfamate of the compound of formula (I).

Preferably, the sodium salt of the compound of formula (I) is a sodiumsalt of topiramate, the compound of formula (Ia).

Preferably, the sodium salt of topiramate is a compound of formula (II)

wherein a sodium cation displaces one of the hydrogen atoms of thesulfamate of the compound of formula (Ia).

In a further embodiment of the present invention is a process forpreparing the sodium salt of a compound of formula (I), preferablytopiramate, a compound of formula (Ia), comprising

-   -   a.) reacting the compound of formula (I) with sodium hydride,        sodium hydroxide, sodium lower alkoxide or sodium amide; in an        organic solvent; or alternatively when the compound of        formula (I) is reacted with sodium hydroxide or sodium lower        alkoxide in an alcohol; and    -   b.) precipitating the product.

More particularly, the compound of formula (I) is reacted with sodiumhydride, under anhydrous conditions, in an inert organic solvent such asTHF, Et₂O, toluene, t-butyl methyl ether (MTBE), and the like,preferably THF; and the product is precipitated.

Alternatively, the compound of formula (I) is reacted with sodiumhydroxide, in an organic solvent such as THF, Et₂O, MTBE, ethyl acetate,isopropyl acetate, methanol, ethanol, and the like; or in a mixture oforganic solvents such as methanol/ethyl acetate, methanol/isopropylacetate, ethanol/ethyl acetate, ethanol/isopropyl acetate, and the like;and the product is precipitated.

Alternatively still, the compound of formula (I) is reacted with asodium lower alkoxide such as sodium methoxide, sodium ethoxide; sodiumpropoxide, sodium t-butoxide, and the like; preferably sodium methoxide,preferably under anhydrous conditions, in an organic solvent such asTHF, Et₂O, MTBE, ethyl acetate, isopropyl acetate, methanol, ethanol,and the like, or in a mixture organic solvents such as methanol/ethylacetate, methanol/isopropyl acetate, ethanol/ethyl acetate,ethanol/isopropyl acetate, and the like, preferably in a mixture ofmethanol/isopropyl acetate; and the product is precipitated.

Alternatively still, the compound of formula (I) is reacted with sodiumamide, under anhydrous conditions, in an organic solvent such as THF,Et₂O, and the like; and the product is precipitated.

The sodium salt product may be precipitated with an anti-solvent such ashexane, pentane, heptane, cyclohexane, and the like, preferably hexane,preferably at a reduced temperature in the range of about 25 to about−20° C. Alternatively, the sodium salt product may be precipitated byevaporation of the solvent.

The sodium salt product may be crystallized or recrystallized from anorganic solvent such as ethyl acetate, methyl acetate, isopropylacetate, and the like, or from a mixture of an alcohol and an organicsolvent such as methanol/ethyl acetate, methanol/isopropyl actetate,ethanol/isopropyl acetate, ethanol/ethyl actetate, and the like,preferably from ethyl acetate or isopropyl acetate; optionally heatingto fully dissolve the solid; adding water, preferably in an amount equalto or greater than about 2 equivalents, more preferably in an amountequal to about 3-5 equivalents, most preferably in an amount equal toabout 3 equivalents; and cooling.

Alternatively, the sodium salt product may be crystallized orrecrystallized from an organic solvent such as ethyl acetate, methylacetate, isopropyl acetate, and the like, or from a mixture of analcohol and an organic solvent such as methanol/ethyl acetate,methanol/isopropyl acetate, ethanol/isopropyl acetate, ethanol/ethylacetate, and the like, preferably from ethyl acetate; by heating tofully dissolve the solid and then cooling.

In another embodiment of the invention is a potassium salt of a compoundof formula (I). Preferably, the potassium salt of the compound offormula (I) is a salt wherein a potassium cation displaces one hydrogenatom of the sulfamate of the compound of formula (I)

Preferably, the potassium salt of the compound of formula (I) is apotassium salt of topiramate, the compound of formula (Ia).

Preferably, the potassium salt of topiramate, the compound of formula(Ia), is a compound of formula (III)

wherein a potassium cation displaces one hydrogen atom of the sulfamateof the compound of formula (Ia).

In a further embodiment of the present invention is a process forpreparing the potassium salt of a compound of formula (I), preferablytopiramate, a compound of formula (Ia), comprising

-   -   a.) reacting the compound of formula (I) with potassium hydride,        potassium hydroxide, potassium lower alkoxide or potassium        amide, in an organic solvent or alternatively when the compound        of formula (I) is reacted with potassium hydroxide or potassium        lower alkoxide, in an alcohol; and    -   b.) precipitating the product.

More particularly, the compound of formula (I) is reacted with potassiumhydride, under anhydrous conditions, in an inert organic solvent such asTHF, Et₂O, MTBE, toluene, and the like, preferably THF; and the productis precipitated.

Alternatively, the compound of formula (I) is reacted with potassiumhydroxide, in an organic solvent such as THF, Et₂O, MTBE, ethyl acetate,isopropyl acetate, methanol, ethanol, and the like, or in a mixture oforganic solvents such as methanol/ethyl acetate, methanol/isopropylacetate, ethanol/ethyl acetate, ethanol/isopropyl acetate, and the like,preferably in an alcohol such as ethanol; and the product isprecipitated.

Alternatively still, the compound of formula (I) is reacted with apotassium lower alkoxide such as potassium methoxide, potassiumethoxide, potassium propoxide, potassium t-butoxide, and the like,preferably potassium ethoxide; preferably under anhydrous conditions, inan organic solvent such as THF, Et₂O, MTBE, methanol, ethanol, and thelike, or in a mixture of organic solvents such as methanol/ethylacetate, methanol/isopropyl acetate, ethanol/ethyl acetate,ethanol/isopropyl acetate, and the like, preferably in ethanol; and theproduct is precipitated.

Alternatively still, the compound of formula (I) is reacted withpotassium amide, under anhydrous conditions, in an inert organic solventsuch as THF, Et₂O, and the like; and the product is precipitated.

The potassium salt product may be precipitated with an anti-solvent suchas hexane, pentane, heptane, cyclohexane, and the like, preferablyhexane, preferably at a reduced temperature in the range of about 25 toabout −20° C. Alternatively, the potassium salt product may beprecipitated by evaporation of the solvent.

The potassium salt product may be crystallized or recrystallized from anorganic solvent such as ethyl acetate, methyl acetate, isopropylacetate, methanol, ethanol, isopropyl alcohol, and the like, or from amixture of organic solvents such as methanol/ethyl acetate,methanol/isopropyl actetate, ethanol/isopropyl acetate, ethanol/ethylactetate, and the like, preferably from a mixture of ethylacetate/methanol or ethanol, by heating to fully dissolve the solid, andcooling.

In another embodiment of the invention is a lithium salt of a compoundof formula (I). Preferably, the lithium salt of the compound of formula(I) is a salt wherein a lithium cation displaces one hydrogen atom ofthe sulfamate of the compound of formula (I).

Preferably, the lithium salt of the compound of formula (I) is a lithiumsalt of topiramate, the compound of formula (Ia).

Preferably, the lithium salt of topiramate is a compound of formula (IV)

wherein a lithium cation displaces one hydrogen atom of the sulfamate ofthe compound of formula (Ia).

In a further embodiment of the present invention is a process forpreparing the lithium salt of a compound of formula (I), preferablytopiramate, a compound of formula (Ia), comprising

-   -   a.) reacting the compound of formula (I) with lithium hydride,        lithium hydroxide, lithium lower alkoxide, alkyl lithium or        lithium amide, in an organic solvent or alternatively when the        compound of formula (I) is reacted with lithium hydroxide or        lithium lower alkoxide, in an alcohol; and    -   b.) precipitating the product.

More particularly, the compound of formula (I) is reacted with lithiumhydride, under anhydrous conditions, in an inert organic solvent such asTHF, Et₂O, MTBE, and the like, preferably THF; and the product isprecipitated.

Alternatively, the compound of formula (I) is reacted with lithiumhydroxide, in an organic solvent such as THF, Et₂O, MTBE, ethyl acetate,isopropyl acetate, methanol, ethanol, and the like, or in a mixture oforganic solvents such as methanol/ethyl acetate, methanol/isopropylacetate, ethanol/ethyl acetate, ethanol/isopropyl acetate, and the like;preferably under anhydrous conditions, and the product is precipitated.

Alternatively still, the compound of formula (I) is reacted with alithium lower alkoxide such as lithium methoxide, lithium ethoxide,lithium propoxide, lithium t-butoxide, and the like; preferably underanhydrous conditions, in an organic solvent such as THF, Et₂O, MTBE,methanol, ethanol, and the like, or in a mixture of organic solventssuch as methanol/ethyl acetate, methanol/isopropyl acetate,ethanol/ethyl acetate, ethanol/isopropyl acetate, and the like; and theproduct is precipitated.

Alternatively still, the compound of formula (I) is reacted with analkyl lithium such as methyl lithium, ethyl lithium, n-butyl lithium,and the like, preferably n-butyl lithium; under anhydrous conditions, inan inert organic solvent such as THF, Et₂O, MTBE, and the like; and theproduct is precipitated.

Alternatively still, the compound of formula (I) is reacted with lithiumamide, under anhydrous conditions, in an inert organic solvent such asTHF, Et₂O, and the like; and the product is precipitated.

The lithium salt product may be precipitated by evaporation of thesolvent.

In another embodiment of the invention is a magnesium salt of a compoundof formula (I). Preferably, the magnesium salt of the compound offormula (I) is a salt wherein a magnesium cation displaces one hydrogenatom of the sulfamate of the compound of formula (I).

Preferably, the magnesium salt of the compound of formula (I) is amagnesium salt of topiramate, the compound of formula (Ia).

Preferably, the magnesium salt of topiramate is a compound of formula(V):

wherein a magnesium cation displaces one hydrogen atom of the sulfamateof two molecules of the compound of formula (Ia).

In a further embodiment of the present invention is a process forpreparing a magnesium salt of a compound of formula (I), preferablytopiramate, a compound of formula (Ia), comprising

-   -   a.) reacting the compound of formula (I) with magnesium lower        alkoxide; under anhydrous conditions; in an organic solvent; and    -   b.) precipitating the product.

More particularly, the compound of formula (I) is reacted with amagnesium lower alkoxide, such as magnesium methoxide, magnesiumethoxide, magnesium-t-butoxide, and the like, preferably magnesiummethoxide, under anhydrous conditions, in an organic solvent such asethyl acetate, isopropyl acetate, THF, Et₂O, MTBE, methanol, ethanol,and the like, or in a mixture of organic solvents such as methanol/ethylacetate, methanol/isopropyl acetate, ethanol/ethyl acetate,ethanol/isopropyl acetate, and the like, preferably in methanol; andprecipitating the product.

The magnesium salt product may be precipitated with an anti-solvent suchas hexane, pentane, heptane, cyclohexane, and the like, preferablyhexane, preferably at a reduced temperature in the range of about 25 toabout −20° C. Alternatively, the magnesium salt product may beprecipitated by cooling the solution to a temperature in the range ofabout 0 to about −20° C. Alternatively still, the magnesium salt productmay be precipitated by evaporation of the solvent.

The present invention further relates to novel crystalline forms of thecompound of formula (II) and the compound of formula (III) and amorphousforms of the compound of formula (II), the compound of formula (III),the compound of formula (IV) and the compound of formula (V).

In an embodiment of the present invention are novel crystalline forms ofthe compound of formula (II), more particularly Form Na1 and Form Na2;and amorphous Form Na4.

Amorphous Form Na4 of the compound of formula (II) may be characterizedby its physical appearance (foamy solid) and the absence of narrow peaksin the XRD (no XRD pattern).

Amorphous Form Na4 may be prepared by reacting the compound of formula(II) with sodium hydroxide, in an organic solvent, and precipitating theproduct by treating the solution with an anti-solvent or by evaporatingthe solvent under reduced pressure.

Crystalline Form Na1 of the compound of formula (II) may becharacterized by its X-ray diffraction pattern, comprising the peaks:TABLE 1 X-Ray Diffraction Peaks, Na Salt, Form Na1 d-spacing RelativeIntensity Angle (°2θ) (Ångstrom) (%) 4.500 19.6206 100.0 9.020 9.79617.2 11.390 7.7625 1.2 12.065 7.3297 22.4 12.690 6.9701 8.5 13.530 6.539242.3 13.655 6.4796 42.3 14.975 5.9113 12.6 16.120 5.4939 4.8 16.9005.2421 0.9 17.510 5.0608 10.9 18.040 4.9133 56.3 18.420 4.8128 2.919.065 4.6514 32.4 20.050 4.4250 8.7 20.745 4.2783 13.2 21.160 4.19532.7 21.710 4.0903 16.0 22.515 3.9458 17.0 23.600 3.7668 3.7 23.9253.7164 11.3 24.445 3.6385 32.1 24.985 3.5611 1.7 25.665 3.4682 5.026.420 3.3708 7.8 27.315 3.2624 36.8 27.765 3.2105 18.0 28.260 3.155411.3 29.735 3.0021 12.9 30.065 2.9699 3.7 30.870 2.8943 12.2 31.3552.8506 2.4 31.800 2.8117 7.3 32.805 2.7279 8.9 33.035 2.7094 7.0 33.6402.6620 4.8 34.805 2.5755 18.2

Crystalline Form Na1 of the compound of formula (II) may be furthercharacterized by its X-ray diffraction pattern, comprising the majorpeaks: TABLE 2 X-Ray Diffraction Peaks, Na Salt, Form Na1 d-spacingRelative Intensity Angle (°2θ) (Ångstrom) (%) 4.500 19.6206 100.0 12.0657.3297 22.4 13.530 6.5392 42.3 13.655 6.4796 42.3 14.975 5.9113 12.617.510 5.0608 10.9 18.040 4.9133 56.3 19.065 4.6514 32.4 20.745 4.278313.2 21.710 4.0903 16.0 22.515 3.9458 17.0 23.925 3.7164 11.3 24.4453.6385 32.1 27.315 3.2624 36.8 27.765 3.2105 18.0 28.260 3.1554 11.329.735 3.0021 12.9 30.870 2.8943 12.2 34.805 2.5755 18.2

Crystalline Form Na1 may be prepared according to the process outlinedabove, reacting the compound of formula (Ia) with sodium hydride, sodiumhydroxide or sodium lower alkoxide, in an organic solvent or mixturethereof; optionally evaporating the solvent to precipitate the product;and crystallizing or recrystallizing in an organic solvent such as ethylacetate, isopropyl acetate, and the like or a mixture of organicsolvents such as methanol/ethyl acetate, ethanol/ethyl acetate,methanol/isopropyl acetate, ethanol/isopropyl acetate, preferablymethanol/isopropyl acetate, optionally heating to fully dissolve thesolid, and then adding water, preferably in the amount equal to orgreater than about 2 equivalents, more preferably in an amount equal toabout 3-5 equivalents, most preferably in an amount equal to about 3equivalents, and cooling.

Alternatively, crystalline Form Na1 may be prepared by subjectingamorphous form Na4 to elevated humidity conditions.

Crystalline Form Na2 of the compound of formula (II) may becharacterized by its X-ray diffraction pattern, comprising the peaks:TABLE 3 X-Ray Diffraction Peaks, Na Salt, Form Na2 d-spacing RelativeIntensity Angle (°2θ) (Ångstrom) (%) 4.450 19.8409 7.6 5.080 17.381789.5 8.025 11.0084 3.7 8.805 10.0348 4.1 9.980 8.8559 2.5 11.545 7.658742.6 11.980 7.3815 7.4 12.375 7.1468 11.1 13.625 6.4938 71.9 15.2555.8034 53.3 17.605 5.0337 13.3 17.990 4.9268 15.6 18.460 4.8024 14.319.040 4.6574 100.0 19.840 4.4714 11.4 21.115 4.2042 29.5 21.240 4.179719.2 22.325 3.9790 12.2 22.835 3.8913 15.8 23.890 3.7217 9.8 25.0403.5534 17.4 25.665 3.4682 35.7 27.305 3.2635 11.4 28.060 3.1774 7.428.860 3.0911 8.6 29.555 3.0200 7.3 30.495 2.9290 12.2 31.740 2.816915.0 32.450 2.7569 7.4 32.980 2.7138 10.1 33.980 2.6362 8.8

Crystalline Form Na2 of the compound of formula (II) may be furthercharacterized by its X-ray diffraction pattern, comprising the majorpeaks: TABLE 4 X-Ray Diffraction Peaks, Na Salt, Form Na2 d-spacingRelative Intensity Angle (°2θ) (Ångstrom) (%) 5.080 17.3817 89.5 11.5457.6587 42.6 12.375 7.1468 11.1 13.625 6.4938 71.9 15.255 5.8034 53.317.605 5.0337 13.3 17.990 4.9268 15.6 18.460 4.8024 14.3 19.040 4.6574100.0 19.840 4.4714 11.4 21.115 4.2042 29.5 21.240 4.1797 19.2 22.3253.9790 12.2 22.835 3.8913 15.8 25.040 3.5534 17.4 25.665 3.4682 35.727.305 3.2635 11.4 30.495 2.9290 12.2 31.740 2.8169 15.0 32.980 2.713810.1

Crystalline Form Na2 may be prepared by recrystallizing the crystallineForm Na1 from an anhydrous organic solvent, such as ethyl acetate,methyl acetate, isopropyl acetate, and the like, preferably ethylacetate, without addition of water, by heating and cooling.

The crystalline form of the compound of formula (II), specifically FormNa1 is a tri-hydrate, whereas the crystalline form of the compound offormula (II), specifically Form Na2 is a non-hydrate, as determined byKarl-Fischer measurements of weight % water, as listed in Table 5. TABLE5 KARL-FISCHER VALUES, Na Salts % % Form Water Meas. Water Theor.Hydrate Form Na1 13.0-14.2% 13% tri-hydrate Na2 1.64%  0% non-hydrate

In another embodiment of the present invention are novel crystallineforms of the compound of formula (III), more particularly Form K1 andForm K2; and amorphous Form K3.

Amorphous Form K3 of the compound of formula (III) may be characterizedby its physical appearance (foamy solid) and the absence of narrow peaksin the XRD (no XRD pattern).

Amorphous Form K3 may be prepared by reacting the compound of formula(Ia) with potassium hydroxide, in an organic solvent, and precipitatingthe product by evaporating the solvent.

Crystalline Form K1 of the compound of formula (III) may becharacterized by its X-ray diffraction pattern, comprising the peaks:TABLE 6 X-Ray Diffraction Peaks, K Salt, Form K1 d-spacing RelativeIntensity Angle (°2θ) (Ångstrom) (%) 4.975 17.7483 100.0 5.830 15.147243.3 7.895 11.1893 6.5 9.940 8.8914 17.6 10.460 8.4505 3.1 11.695 7.56084.1 12.270 7.2077 4.6 12.730 6.9483 2.2 13.115 6.7452 2.7 13.560 6.524812.4 14.120 6.2673 1.1 14.930 5.9290 31.2 15.245 5.8072 27.2 15.8355.5921 2.2 16.135 5.4888 1.5 17.225 5.1439 3.9 17.645 5.0224 7.2 17.9154.9473 17.3 18.420 4.8128 2.8 18.660 4.7514 3.9 19.060 4.6526 2.0 19.3554.5823 4.5 19.960 4.4448 9.5 20.890 4.2490 50.6 21.510 4.1279 3.0 21.9954.0379 4.0 23.475 3.7866 15.0 25.210 3.5298 35.6 25.755 3.4563 5.026.525 3.3577 6.5 27.265 3.2682 2.3 27.975 3.1869 5.2 28.605 3.1181 4.229.535 3.0220 3.9 30.105 2.9661 18.4 30.290 2.9484 14.4 30.760 2.90444.7 31.265 2.8586 3.4 31.710 2.8195 4.4 32.630 2.7421 2.0 32.895 2.72062.9 33.810 2.6490 4.3 34.165 2.6223 7.2

Crystalline Form K1 of the compound of formula (III) may be furthercharacterized by its X-ray diffraction pattern, comprising the majorpeaks: TABLE 7 X-Ray Diffraction Peaks, K Salt, Form K1 d-spacingRelative Intensity Angle (°2θ) (Ångstrom) (%) 4.975 17.7483 100.0 5.83015.1472 43.3 9.940 8.8914 17.6 13.560 6.5248 12.4 14.930 5.9290 31.215.245 5.8072 27.2 17.915 4.9473 17.3 20.890 4.2490 50.6 23.475 3.786615.0 25.210 3.5298 35.6 30.105 2.9661 18.4 30.290 2.9484 14.4

Crystalline Form K2 of the compound of formula (III) may becharacterized by its X-ray diffraction pattern, comprising the peaks:TABLE 8 X-Ray Diffraction Peaks, K Salt, Form K2 d-spacing RelativeAngle (°2θ) (Ångstrom) Intensity (%) 4.430 19.9304 100.0 4.940 17.87398.1 5.785 15.2649 10.2 6.275 14.0739 11.9 7.020 12.5819 18.9 7.83511.2749 4.4 9.430 9.3711 16.4 9.915 8.9138 5.1 11.345 7.7932 23.5 12.2057.2460 6.7 12.715 6.9565 18.1 13.475 6.5658 24.4 13.805 6.4095 21.814.090 6.2805 15.5 14.875 5.9508 17.9 15.220 5.8167 12.4 15.505 5.710418.5 15.770 5.6150 23.8 16.495 5.3698 22.2 16.920 5.2359 15.6 17.3555.1056 29.9 17.920 4.9459 22.9 18.495 4.7934 19.3 19.150 4.6309 18.719.795 4.4815 34.9 20.200 4.3925 50.1 20.780 4.2712 19.3 21.485 4.132613.2 21.975 4.0416 9.9 22.320 3.9799 19.1 22.705 3.9132 18.7 23.4553.7898 11.1 24.040 3.6989 22.0 24.720 3.5986 12.5 25.070 3.5492 13.725.555 3.4829 16.2 25.995 3.4249 18.9 26.570 3.3521 10.8 27.240 3.271221.1 27.865 3.1992 19.1 28.330 3.1477 14.7 28.860 3.0911 12.0 29.2853.0472 14.7 30.880 2.8934 15.1 31.965 2.7976 14.4 32.955 2.7158 9.634.235 2.6171 9.6

Crystalline Form K2 of the compound of formula (III) may be furthercharacterized by its X-ray diffraction pattern, comprising the majorpeaks: TABLE 9 X-Ray Diffraction Peaks, K Salt, Form K2 d-spacingRelative Angle (°2θ) (Ångstrom) Intensity (%) 4.430 19.9304 100.0 5.78515.2649 10.2 6.275 14.0739 11.9 7.020 12.5819 18.9 9.430 9.3711 16.411.345 7.7932 23.5 12.715 6.9565 18.1 13.475 6.5658 24.4 13.805 6.409521.8 14.090 6.2805 15.5 14.875 5.9508 17.9 15.220 5.8167 12.4 15.5055.7104 18.5 15.770 5.6150 23.8 16.495 5.3698 22.2 16.920 5.2359 15.617.355 5.1056 29.9 17.920 4.9459 22.9 18.495 4.7934 19.3 19.150 4.630918.7 19.795 4.4815 34.9 20.200 4.3925 50.1 20.780 4.2712 19.3 21.4854.1326 13.2 21.975 4.0416 9.9 22.320 3.9799 19.1 22.705 3.9132 18.723.455 3.7898 11.1 24.040 3.6989 22.0 24.720 3.5986 12.5 25.070 3.549213.7 25.555 3.4829 16.2 25.995 3.4249 18.9 26.570 3.3521 10.8 27.2403.2712 21.1 27.865 3.1992 19.1 28.330 3.1477 14.7 28.860 3.0911 12.029.285 3.0472 14.7 30.880 2.8934 15.1 31.965 2.7976 14.4 32.955 2.71589.6 34.235 2.6171 9.6

Crystalline Form K1 and Form K2 may be prepared by recrystallizing theamorphous Form K3. More particularly, crystalline Form K1 may beprepared by recrystallizing amorphous Form K3 from an organic solvent ormixture thereof, preferably an ethyl acetate/methanol mixture whereinthe percent methanol is greater than or equal to about 5%, by heatingand cooling.

Alternatively, crystalline Form K1 may be prepared by recrystallizingamorphous Form K3, crystalline Form K2 or a mixture thereof, from anorganic solvent such as ethyl acetate, isopropyl acetate, ethanol,methanol, and the like, or from a mixture thereof, such asethanol/isopropyl acetate, ethanol/ethyl acetate, and the like,preferably from ethanol, by heating and cooling.

Crystalline Form K2 may be prepared by recrystallizing amorphous Form K3from an organic solvent or mixture thereof, preferably an ethylacetate/methanol mixture wherein the percent methanol is less than about5%, by heating and cooling.

Alternatively, crystalline Form K2 may be prepared by recrystallizingamorphous Form K3 from an organic solvent or mixture thereof, preferablyan ethyl acetate/methanol mixture wherein the percent methanol isgreater than about 5%, by heating the mixture to evaporate excessmethanol, as measured by an increase in boiling temperature to greaterthan about 70° C. and cooling.

Crystalline Form K1 and Form K2 of the compound of formula (III) arenon-hydrates, as determined by Karl-Fischer measurements of weight %water, as listed in Table 10. TABLE 10 KARL-FISCHER VALUES, K SALTS % %Form Water Meas. Water Theor. Hydrate Form K1 0.16% 0% non-hydrate K21.09% 0% non-hydrate

In another embodiment of the present invention is an amorphous form ofthe compound of formula (IV), more particularly Form Li1.

Amorphous Form Li1 of the compound of formula (IV) may be characterizedby its physical appearance (foamy solid) and the absence of narrow peaksin the XRD (no XRD pattern).

Amorphous Form Li1 may be prepared by reacting the compound of formula(Ia) with lithium hydroxide in an organic solvent or with an alkyllithium in an inert organic solvent under anhydrous conditions; andprecipitating the product by evaporation of solvent.

In yet another embodiment of the present invention is an amorphous formof the compound of formula (V), more particularly Form Mg1.

Amorphous Form MG1 of the compound of formula (V) may be characterizedby its physical properties (foamy solid) and by the absence of narrowpeaks in the XRD (no XRD pattern).

Amorphous Form Mg1 may be prepared by reacting the compound of formula(Ia) with a magnesium lower alkoxide, in an organic solvent, andprecipitating the product with an anti-solvent or by evaporating thesolvent under reduced pressure.

As used herein, the term “subject” shall refer to an animal, preferablya mammal, more preferably a human, who is the object of treatment,observation of experiment.

As used herein, the term “therapeutically effective amount”, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

The salts of the instant invention may be administered to a subject inneed thereof at any dosage level such that the amount is therapeuticallyeffective. Optimal dosages to be administered may be readily determinedby those skilled in the art, and will vary with the particular saltused, the mode of administration, the strength of the preparation, andthe advancement of the disease condition. In addition, factorsassociated with the particular patient being treated, including patientage, weight, diet and time of administration, will result in the need toadjust dosages.

The present invention further provides a method of treating epilepsy ina subject in need thereof which comprises administering any of the saltsas defined herein in a therapeutically effective amount. Preferably, fortreating epilepsy, the salts are administered in a dosage range of about10 to 650 mg/daily, more preferably in the range of about 16 to 325mg/once or twice daily.

The salts of the instant invention may be administered by any suitablemethod, as would be apparent to one skilled in the art. Moreparticularly, the salts of the compound of formula (I) may beadministered by any parenteral method including, but not limited to, viaoral, pulmonary, intraperitoneal (ip), intramuscular (im), intravenous(iv), subcutaneous (sc), transdermal, buccal, nasal, sublingual, ocular,rectal and vaginal routes of administration. The salts of the compoundof formula (I) may also be administered directly to the nervous systemvia intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal and/or peri-spinal routes ofadministration, with or without pump devices. It will be readilyapparent to those skilled in the art that any dose or frequency ofadministration that provides the desired therapeutic effect is suitablefor use in the instant invention.

To prepare the pharmaceutical compositions of the present invention, oneor more of the salts described herein are intimately admixed with apharmaceutical carrier according to conventional techniques, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral, by suppository orparenteral. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixers and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservative, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit form, in which casesolid pharmaceutical carriers are obviously employed. If desired,tablets may be sugar coated or enteric coated by standard techniques.Suppositories may be prepared, in which cocoa butter could be used as acarrier. For parenterals, the carrier will usually comprise sterilewater, though other ingredients, for example, for purposes such asaiding solubility or for preservation, may be included. Injectablesuspensions may also be prepared in which case, appropriate liquidcarriers, suspending agents and the like may be employed.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful, suppository andthe like, from about 10 to about 500 mg of active ingredient.

The following examples describe the invention in greater detail and areintended to illustrate the invention, but not to limit it.

EXAMPLE 1 Potassium Salt—Form K2

Topiramate (853.6 mg) was dissolved in THF (2.5 mL). The solution waschilled in an ice bath. To the solution was then added 1M potassiumbutoxide in THF (2.5 mL) dropwise. The solution was stirred for 30 min.A precipitate was formed. The precipitate was filtered and placed in avacuum oven at 34° C., to yield the potassium salt as Form K2, as asolid.

EXAMPLE 2 Potassium Salt—Form K2

Topiramate (1.0007 g, 2.95 mmol) was dissolved in diethyl ether (20 mL).The solution was chilled in an ice water bath under N₂. 1M potassiumtert-butoxide in THF (2.95 mL, 2.95 mmol) was the added dropwise to thesolution. The solution was stirred for 30 min and a precipitate wasformed. The precipitate was filtered under N2, washed with additionaldiethyl ether and dried in a vacuum oven at ambient temperature to yieldthe potassium salt product as Form K2, as a white solid.

EXAMPLE 3 Potassium Salt—Form K3

Topiramate (0.7512 g) was dissolved in toluene (15 mL). Potassiumhydroxide (0.1440 g) was added and the solution was stirred at 360 rpm.A Dean Stark trap was attached and the hot plate temperature increaseduntil the toluene was a rapid reflux (at about 185° C.). The solutionwas maintained at reflux for 24 hours. The solution was allowed to coolslowly, then filtered. The remaining solvent was removed byroto-evaporation in a water bath set at 30° C. Solids remaining in theflask were dissolved in ethyl acetate (2 mL). To the solution was thenadded hexanes (15 mL), resulting in the formation of a precipitate. Theprecipitate was collected by vacuum filtration and washed with diethylether (30 mL), to yield the potassium salt as Form K3, as a solid. Thesolid was stored over P₂O₅.

EXAMPLE 4 Sodium Salt—Form Na1

Sodium hydride (71.1 mg) (60% dispersion in mineral oil) was rinsed 3times with pentane and dried under N₂ for 30 min. A solution oftopiramate (500 mg) dissolved in THF (3 mL) was added dropwise. Anadditional solution of topiramate (103 mg) in THF (2 mL) was then added.The solution was stirred in an ice water bath under N₂ overnight. To thesolution was added hexane (4 mL) and the solution was again stirredovernight, resulting in the formation of a cloudy precipitate. Thesolution was placed in a refrigerator and then into a freezer overnight.The solution was removed from the freezer and then stirred at ambienttemperature for about 3 hours. The resulting precipitate was collectedby vacuum s filtration and air dried to yield the sodium salt as FormNa1, as a solid.

EXAMPLE 5 Sodium Salt—Form Na3

Sodium hydride (0.1076 g) (60% dispersion in mineral oil) was rinsedwith hexanes (30 mL) under N₂. The upper layer of the solution wasremoved with a dry pipette. The remaining hexanes were evaporated byfast evaporation under N₂ for about 1 hour. THF (2 mL) was then added tothe sodium hydride slurry and the resulting slurry was cooled in an icewater bath. A solution of topiramate (853.8 mg) in THF (2.5 mL) wasadded dropwise to the cold sodium hydride slurry. Hexanes (25 mL) werethen added to the mixture, resulting in the formation of a precipitate.The precipitate was vacuum filtered, washed with additional hexanes andthen placed in a vacuum oven at 34° C. for about 1 hr.

The resulting solid was mixed with diethyl ether (40 mL) and sonicated.The solution was vacuum filtered and the precipitate dried in a vacuumoven at 34° C., to yield the sodium salt as Form Na3, as a solid.

EXAMPLE 6 Sodium Salt—Form Na4

Sodium hydride (507 mg) was rinsed 4 times with pentane (10 mL) and thenallowed to dry under a N₂ stream. A solution of topiramate (3.5 g) inTHF (10 mL) was then added to the sodium hydride and stirred at roomtemperature. The solution was cooled in a dry ice/isopropyl alcohol bathand then allowed to warm to room temperature. The solution was filteredthrough an 0.2 m nylon filter. The solution was then allowed to standunder N₂ stream overnight, to slowly evaporate the solvent. To theresidue were added hexanes (15 mL). The resulting mixture was sonicatedand the vessel sides scratched to induce precipitation of product. THF(1.5 mL) was added and the slurry stirred at ambient temperature, andlet stand under N₂ for 2 days. The resulting precipitate was collectedby vacuum filtration, rinsed 3 times with hexanes (5 mL) and placed for6 hours in a vacuum oven at ambient temperature, to yield the sodiumsalt as Form Na4, as a solid. The sold was lightly ground with agatemortal and pestle prior to testing.

EXAMPLE 7 Preparation of Sodium Salt Form Na4

Topiramate (3.4 g, 10 mmol) was dissolved in THF (40 mL) at roomtemperature, then treated with 50% aq NaOH (0.8 g, 10 mmol). At the endof addition, a clear solution was formed. The THF was evaporated underreduced pressure and the oily residue placed under vacuum to remove anyremaining solvent or water. The product formed as a white foam, anamorphous solid. XRD-analysis confirmed that the product was amorphous.

EXAMPLE 8 Preparation of Sodium Salt Form Na1

Topiramate (3.39 g, 10 mmol) in THF (50 mL) was treated with sodiumethoxide (21wt %, 3.24 g, 10 mmol) and the mixture was stirred at roomtemp. The ethanol was evaporated, the residue dissolved in t-butylmethyl ether (100 mL) and treated with H₂O (˜0.4 g), resulting in theformation of a crystalline solid. The solid was collected by filtrationand air-dried (3.9 g in two crops). The solid was suspended in ethylacetate (30 mL) and heated, just enough to dissolve the solid withoutloosing any water. The solution was filtered quickly through a smallcotton plug and allowed to stand at room temperature. The productcrystallized out over about 20 min. The solid was collected byfiltration, washed with a small amount of ethyl acetate and air-dried.

Water (wt % by KF): 14.2%.

EXAMPLE 9 Preparation of Sodium Salt Form Na1

Sodium hydride (95%, 0.51 g, 20 mmol) was suspended in THF (100 mL) atroom temperature. Topiramate (6.78 g, 20 mmol) was added portion-wise tothe suspension. At the end of addition, a nearly clear solution wasformed. The solution was filtered quickly through a small cotton plugand the THF was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (50 mL) and water (1 g). The solution wasallowed to stand at room temperature where the product started tocrystallize out, then cooled in an ice-bath. The solid was collected byfiltration, washed with a small amount of ethyl acetate and air-dried.

Water (wt % by KF): 13.5%.

EXAMPLE 10 Preparation of Sodium Salt Form Na1 and Na2

Topiramate (13.56 g, 40 mmol) was dissolved in THF (120 mL) at roomtemperature then treated with 50% aq NaOH (3.2 g, 40 mmol). At the endof addition, a clear solution was formed. The THF was evaporated underreduced pressure and the residue was dissolved in ethyl acetate (150mL). Water (about 2 g) was added to the solution with stirring. Theproduct started to crystallize out soon after. The mixture was allowedto stand at room temperature for 15 min, then cooled in an ice-bath toabout 5° C. The product, as Form Na1, was collected by filtration,washed with ethyl acetate and air-dried.

Water (wt % by KF): 13.58%

Recrystallization to Prepare Form Na2:

A sample of the product (3 g, 7.2 mmol) was mixed with ethyl acetate (50mL) and heated on a steam bath until the solid dissolved. The hazysolution was hot-filtered and then allowed to stand at room temperature.The product crystallized out as a white solid; the mixture was furthercooled in an ice bath. The solid was collected by filtration and rinsedwith cold ethyl acetate (10 mL) then air-dried to yield the product asForm Na2.

Water 1.64 wt % by KF analysis

EXAMPLE 11 Preparation of Potassium Salt Form K1

Potassium hydroxide (85%, 0.66 g, 10 mmol) was stirred in ethanol (50mL) at room temperature together with topiramate (3.39 g, 10 mmol). Allsolids dissolved in a few minutes. The solvent was evaporated underreduced pressure. The residue was dissolved in ethyl acetate (50 mL) andwater (0.4 g) and allowed to stand. The solution was then cooled in anice-bath, a white solid crystallized out. The solid was collected byfiltration, washed with a small amount of ethyl acetate and air-dried.

Water (wt % by KF): 1.7%.

EXAMPLE 12 Preparation of Potassium Salt Form K1

Potassium hydroxide (85%, 0.1.32 g, 20 mmol) was dissolved in H₂O (2 mL)at room temperature. Topiramate (6.78 g, 20 mmol) in ethyl acetate (75mL) was added to the KOH and the mixture stirred at room temperature toyield a clear solution. The solvent was evaporated under reducedpressure, the residue was re-dissolved in ethyl acetate (150 mL) andallowed to stand. The solution was then cooled in an ice-bath, a whitesolid crystallized out. The solid was collected by filtration, washedwith ethyl acetate and air-dried.

Water (wt % by KF): 0.24%.

Recrystallization:

A sample of the product (2 g, 5.3 mmol) was suspended in ethyl acetate(50 mL) and methanol (5 mL) and the mixture heated on a steam bath untilthe solid dissolved. Heating was continued to evaporate some of themethanol and the resulting solution was allowed to stand at roomtemperature. The product crystallized out as a white solid, which wascollected by filtration and air-dried.

Water (wt %, by KF): 0.23%.

EXAMPLE 13 Preparation of Potassium Salt Form K1

Potassium tert-butoxide (1M in THF, 30 mmol) was s added to a solutionof topiramate (10.2 g, 30 mmol) in THF (75 mL) and the mixture stirredat room temperature to yield a clear solution. The solvent wasevaporated under reduced pressure and the residue dissolved in ethylacetate (150 mL) and methanol (20 mL). The solution was heated toevaporate some of the methanol (the boiling point was observed to risefrom 64 to 70° C.). The solution was allowed to stand, a part of theproduct crystallized out. The solid was collected by filtration, washedwith ethyl acetate and air-dried.

Water (wt % by KF): 0.24%

The filtrate was concentrated and allowed to stand at room temperatureto yield a second crop.

EXAMPLE 14 Preparation of Potassium Salt Form K1 and K2

Potassium hydroxide (85%, 7.26 g, 110 mmol) was added at roomtemperature to a solution of topiramate (39 g, 115 mmol) in THF (250 mL)and methanol (50 mL). The reaction mixture was stirred at roomtemperature for 30 min, until all of the KOH had dissolved to yield aclear solution. The solvent was evaporated under reduced pressure andthe oily residue (51.2 g) was mixed with ethyl acetate (300 mL) andmethanol (15 mL) and then heated on a steam bath. The residue became awhite solid, then completely dissolved to yield a clear solution. Thesolution was allowed to cool to room temperature, seeded with a fewcrystals of K-salt and left to stand at room temperature overnight. Thesolid was collected by filtration, washed with ethyl acetate andair-dried, to yield Form K1, as a solid.

Karl-Fischer % wt water: 0.16%

The filtrate was heated to remove most of the methanol (bp rose from 64°C. to 75° C. and the total volume was reduced to 300 mL). The solutionwas allowed to stand at room temperature for about 1 h, a hard whitesolid-precipitated and was broken down before filtration. The solid wasrinsed with ethyl acetate and air-dried, to yield K2 as a solid. Thesolid initially behaved as a hygroscopic material (became sticky) beforeit was air-dried; after drying there were no hygroscopic properties.

Karl-Fischer % wt water: 1.09%

EXAMPLE 15 Preparation of Potassium Salt Form K3

Potassium hydroxide (85%, 13.2 g, 200 mmol) was dissolved in water (25mL) and added at room temperature to a solution of topiramate (68.6 g,202 mmol) in THF (500 mL), then stirred at room temperature for 10 min.The solvent was evaporated under reduced pressure to yield a foamy solid(80.9 g). XRD analysis confirmed the solid was amorphous.

EXAMPLE 16 Preparation of Lithium Salt Form Li1

n-Butyl lithium (10 mL of 2M solution in cyclohexane, 20 mmol) was addedslowly to a solution of topiramate (7.0 g, 20.6 mmol) in THF (50 mL) atabout 25-35° C. The solvent was evaporated under reduced pressure toyield a foamy, light yellow, amorphous solid. XRD analysis confirmed thesolid was amorphous.

EXAMPLE 17 Preparation of Magnesium Salt Form Mg1

Magnesium turnings (0.24 g 10 matm) in methanol (100 mL) were heated ona steam bath until the Mg dissolved. Topiramate (6.78 g, 20 mmol) wasadded to the Mg-methoxide solution and heated on a steam bath for about5 min, then cooled to room temperature. Any contact with water wasavoided. The solvent was evaporated under reduced pressure and theresidue further dried under vacuum at room temperature to a constantweight, to yield the product as a white foamy amorphous solid. XRDanalysis confirmed the solid was amorphous.

EXAMPLE 18 Preparation of Sodium Salt Form Na1

Topiramate (50 g, 0.147 mol) was dissolved in isopropyl acetate (600 mL)and treated with 30% NaOCH₃ in methanol (28.5 mL). The light yellowsolution was heated at reflux to distill some of the solvent (anazeotrope of methanol/isopropyl acetate, 70.2/29.8, bp. 64° C.) till thetemperature in the flask was observed to reach 85° C. The reactionmixture was then cooled to about 20-25° C. The reaction mixture wasfiltered through Celite (to remove any insoluble residue) and rinsedwith isopropyl acetate (60 mL). The solution was then heated to 50° C.To the solution was added water (7.9 ml) over 1 min. The product wasallowed to crystallize at about 20-25° C. overnight. The solid wascollected by filtration, washed with isopropyl acetate (50 ml) and driedin a vacuum oven containing a bowl of water at 30° C. for 24 h.

Water (wt % by KF): 13%.

EXAMPLE 19 Preparation of Sodium Salt Form Na1

Topiramate (50g, 0.147 mol) was dissolved in isopropyl acetate (367 ml)(2.5 L/mol). Sodium methoxide 30% in methanol (27.2 ml, 1 eq.) was addedat room temperature. The mixture was stirred over 10 min and thenfiltered at about 22-25° C. The filtrate was then heated to 35° C. Water(8 ml, 3 eq.) was then added and the crystallization began afterseeding. The mixture was cooled down to about 22-25° C. over 30 min,then further cooled down with ice-water to about 0-5° C. The precipitatewas filtered off, washed with isopropyl acetate (50 ml) (0.35 L/mol) anddried at 35° C. under vacuum during 18 h.

EXAMPLE 20 Recrystallization of Potassium Salt Form K1

Solid potassium salt of topiramate (66 g; a mixture of two polymorphicforms K2 and K3) was suspended in ethanol (250 mL) and the mixture washeated to boiling until all of the solid dissolved. The hot solution wasfiltered through Celite and the mixture was diluted to a final volume of360 mL with additional ethanol. The clear solution was seeded, whilehot, with a few crystals of Form K1 solid and allowed to stand at roomtemperature without external cooling. As the solution started to cool,the solid product crystallized out slowly. The crystallization flask waskept in a refrigerator overnight and the cold mixture was filtered toisolate the solid product. The crystalline solid was rinsed with coldethanol, then with diethyl ether and then air-dried.

The filtrate was concentrated to about 150 mL and allowed to stand atroom temperature for 2 days. The resulting solid was collected byfiltration, rinsed with cold ethanol and then air-dried. XRD-patternshowed Form K1.

EXAMPLE 21 Preparation of Potassium Salt Form K1

Topiramate (163.8 g, 483 mmol) was suspended in ethanol (500 mL). To themixture was then added potassium ethoxide in ethanol (24%, 168 g, 479mmol). Nearly all the topiramate dissolved by the end of addition (totalvolume ˜750 mL). The initial crystallization resulted in a paste-likesolid. The mixture was heated gently on a steam bath until it becamefluid. Heating was then continued on a hot plate with stirring until allof the solid had dissolved. The hot solution was filtered through Celiteand rinsed with hot ethanol (50 mL). The solution was again heated toboiling to form a clear solution. The solution was seeded with Form K1crystals while hot, then allowed to stand at room temperature overnight.The flask was cooled in an ice bath for 2 h and the solid was collectedby filtration. The solid was rinsed with cold ethanol (100 mL), thenwith diethyl ether, and then air-dried. The solid was further dried in avacuum oven at about 40-50° C. overnight. The XRD pattern showed FormK1.

Water (wt % by KF): 0.14%

The filtrate was concentrated to about 200 mL. The solution was allowedto stand at room temperature to yield a second crop of Form K1.

EXAMPLE 22 Maximal Electroshock (MES) Seizure Test

Anticonvulsant activity was determined using the MES test as describedby Swinyard E A, Woodhead J H, White H S, Franklin M R. Experimentalselection, quantification, and evaluation of anticonvulsants. In Levy RH, et al., eds. Antiepileptic Drugs. 3^(rd) ed. New York: Raven Press,1989:85-102.

In this procedure, a 60-Hz alternating current (mice 50 mA, rats 150 mA)was delivered for 0.2 sec through corneal electrodes by an apparatusthat is capable of precisely regulating current intensity and-duration.The concave side of the electrode (2 mm diameter for mice; 4.0 mmdiameter for rats) was placed on each cornea. The current reliablyproduces, in all rodents, a single convulsive episode that includes, asa component, hind limb tonic extension. Immediately before placement ofcorneal electrodes, a drop of saline (an electrolyte that promotes thedispersion of the current and that reduces lethalities) was placed oneach electrode. Rodents were restrained by hand during this procedureand released immediately after stimulation to permit observation of theconvulsion throughout its entire course.

The test compound or corresponding vehicle was administered to overnightfasted rodents by the oral (gavage) route of administration. (Testcompound or vehicle may alternatively be administered viaintraperitoneal, intravenous, subcutaneous or intramuscular route ofadministration.) Subsequently, electrical stimulation was administeredto the rodents at a time corresponding to the suspected time of peakactivity of the test compound. The test was complete when the entirecourse of the convulsion had been observed (typically, less than 1minute after electrical stimulation), and rodents were then immediatelyeuthanized by carbon dioxide inhalation.

Abolition of the hind-limb tonic extensor component of the seizure wastaken as the endpoint for this test. Absence of this component indicatedthat the test compound has the ability to prevent the spread of seizuredischarge through neural tissue. The ED₅₀ value of the test compound wasthe calculated dose required to block the hind limb tonic-extensorcomponent of the MES-induced seizure in 50% of the rodents tested.

Form K1 of the potassium salt of topiramate (the compound of formula(Ia)) was tested in rats according to the above procedure, dosingorally. Calculated ED₅₀ value was determined in two separatemeasurements as 3.1 mg/kg and 8.1 mg/kg at 2 hours post dosing.

Form K1 of the potassium salt of topiramate (the compound of formula(Ia)) was tested in mice according to the above procedure, dosing orallyand IP with calculated ED₅₀ results as follows: Dosing orally ED₅₀ @ 2hrs = 40.6 mg/kg Dosing IP ED₅₀ @ 2 hrs = 26.8 mg/kg Dosing IV ED₅₀ @ 5mins = 41.51 mg/kg

Form Na1 of the sodium salt of topiramate (the compound of formula (Ia))was tested in rats according to the above procedure, dosing orally.Calculated ED₅₀ value was determined in as 4.8 mg/kg at 2 hours postdosing.

Form Na1 of the sodium salt of topiramate (the compound of formula (Ia))was tested in mice according to the above procedure, dosing IP withcalculated ED₅₀ results as follows: Dosing IP ED₅₀ @ 30 mins = 45.44mg/kg Dosing IV ED₅₀ @ 5 mins = 46.18 mg/kg

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A salt of a compound of formula (I)

wherein the salt of the compound of formula (I) is formed at thesulfamate groups and wherein the salt is selected from the groupconsisting of magnesium and lithium.
 2. A salt as in claim 1, whereinthe compound of formula (I) is topiramate.
 3. A salt as in claim 1,wherein a lithium or magnesium cation displaces one hydrogen atom of thesulfamate. 4-15. (canceled)
 16. A salt as in claim 1, wherein the saltof the compound of formula (I) is a lithium salt of topiramate.
 17. Asalt as in claim 16, of the formula (IV)


18. A salt as in claim 1, wherein the salt of the compound of formula(I) is a magnesium salt of topiramate.
 19. A salt as in claim 18, of theformula (V)


20. A pharmaceutical composition comprising a salt of claim 1 and apharmaceutically acceptable carrier.
 21. A pharmaceutical compositionprepared by combining a salt of claim 1 and a pharmaceuticallyacceptable carrier.
 22. A process for making a pharmaceuticalcomposition comprising combining a salt of claim 1 with apharmaceutically acceptable carrier. 23-25. (canceled)
 26. A process forpreparing a lithium salt of a compound of formula (I) comprisingreacting a compound of formula (I)

with lithium hydride under anhydrous conditions, lithium hydroxide,lithium lower alkoxide, alkyl lithium under anhydrous conditions orlithium amide under anhydrous conditions, in an organic solvent; andprecipitating the product.
 27. A process for preparing a magnesium saltof a compound of formula (I) comprising reacting a compound of formula(I)

with a magnesium lower alkoxide, under anhydrous conditions, in anorganic solvent; and precipitating the product. 28-30. (canceled)
 31. Aprocess as in claim 26, wherein the compound of formula (I) istopiramate.
 32. A process as in claim 27, wherein the compound offormula (I) is topiramate.